Design and synthesis of P2-P1'-linked macrocyclic human renin inhibitors

J Med Chem. 1991 Sep;34(9):2692-701. doi: 10.1021/jm00113a005.


Using a computer model of the active site of human renin developed at Merck, we designed a series of novel P2-P1'-linked, macrocyclic renin inhibitors 3-10. These unique inhibitors incorporate a transition-state isostere within a 13- or 14-membered ring. The three most active compounds in this family were 13-membered-ring glutamine-derived inhibitor 3, 14-membered-ring diaminopropionic acid derived inhibitor 6, and 13-membered-ring diol 9 (IC50 0.61, 0.59, 0.65 microM, respectively). Modification of inhibitor 3 at P4 led to 56 nM macrocyclic renin inhibitor 39. This study shows the viability of renin inhibitor designs which incorporate a scissile-bond replacement within a macrocycle.

MeSH terms

  • Amino Acid Sequence
  • Computer Simulation
  • Drug Design
  • Humans
  • Hydrogen-Ion Concentration
  • Models, Molecular
  • Molecular Sequence Data
  • Renin / antagonists & inhibitors*
  • Structure-Activity Relationship


  • Renin